Combinations of Organic Compounds

ABSTRACT

The invention provides a pharmaceutical combination comprising:
         a) compounds that inhibit the binding of the Smac protein to IAPs; and   b) a taxane,   and a method for treating or preventing a proliferative disease using such a combination.

The present invention relates to a pharmaceutical combination comprisingcompounds that inhibit the binding of the Smac protein to Inhibitor ofApoptosis Proteins (IAPs) and a taxane, and the uses of such acombination, e.g., in proliferative diseases, e.g., tumors, myelomas andleukemias.

In spite of numerous treatment options for patients with proliferativediseases, there remains a need for effective and safe molecularlytargeted anti-proliferative agents. Combination of such exploratoryagents with existing therapies sometimes results in a synergisticinteraction and enhanced therapeutic benefit relative to either agentalone.

SUMMARY OF THE INVENTION

It has now been found that a combination comprising at least onecompound that inhibits the binding of the Smac protein to IAPs and ataxane, e.g., as defined below, has a beneficial effect on proliferativediseases, e.g., tumors, myelomas and leukemias.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a pharmaceutical combination which comprises:

-   -   (a) a taxane; and    -   (b) a compound (IAP inhibitor) that inhibits the caspase-9        inhibiting properties of an IAP; and, optionally,    -   (c) at least one pharmaceutically acceptable carrier for        simultaneous, separate or sequential use,        in particular, for the treatment of a proliferative disease,        especially a solid tumor disease; a pharmaceutical composition        comprising such a combination; the use of such a combination for        the preparation of a medicament for the treatment of a        proliferative disease; a commercial package or product        comprising such a combination as a combined preparation for        simultaneous, separate or sequential use; and to a method of        treatment of a warm-blooded animal, especially a human. A        greater than additive effect is seen when compounds (a) and (b)        are used in combination.

Taxanes are microtubule targeting agents that bind to tubulin and blockcell division by interfering with the function of the mitotic spindle.Taxanes represent a first line treatment option for metastatic breast,lung, ovarian and digestive cancers and are commonly used in theadjuvant setting for breast cancer.

Taxanes include Paclitaxel, marketed as TAXOL and docetaxel, marketed asTAXOTERE. Other taxanes include vinorelbine and the epothilones, such asepothilone B and patupilone.

Compounds that inhibit the binding of the Smac protein to IAPs includecompounds of the formula (I):

wherein

-   -   R₁ is H, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkynyl or        C₃-C₁₀cycloalkyl, which are unsubstituted or substituted;    -   R₂ is H, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkynyl or        C₃-C₁₀cycloalkyl, which are unsubstituted or substituted;    -   R₃ is H, —CF₃, —C₂F₅, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkynyl,        —CH₂-Z, wherein Z is H, —OH, F, Cl, —CH₃, —CF₃, —CH₂Cl, —CH₂F or        —CH₂OH, or    -   R₂ and R₃, together with the nitrogen, form a het ring;    -   R₄ is C₁-C₁₆straight- or branched-alkyl, C₁-C₁₆alkenyl,        C₁-C₁₆alkynyl or —C₃-C₁₀cycloalkyl, —(CH₂)₁₋₆Z₁, —(CH₂)₀₋₆aryl        and —(CH₂)₀₋₆het, wherein alkyl, cycloalkyl and phenyl are        unsubstituted or substituted,    -   wherein        -   Z₁ is —N(R₈)—C(O)—C₁-C₁₀alkyl,            —N(R₈)—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl,            —N(R₈)—C(O)—(CH₂)₀₋₆phenyl, —N(R₈)—C(O)—(CH₂)₁₋₆het,            —C(O)—N(R₉)(R₁₀), —C(O)—O—C₁-C₁₀alkyl,            —C(O)—O—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆phenyl,            —C(O)—O—CH₂)₁₋₆het, —O—C(O)C₁-C₁₀alkyl,            —O—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —O—C(O)—(CH₂)₀₋₆phenyl,            —O—C(O)—(CH₂)₁₋₆het, wherein alkyl, cycloalkyl and phenyl            are unsubstituted or substituted; and        -   het is a 5- to 7-membered heterocyclic ring containing 1-4            heteroatoms selected from N, O and S, or an 8- to            12-membered fused ring system including at least one 5- to            7-membered heterocyclic ring containing 1, 2 or 3            heteroatoms selected from N, O, and S, which heterocyclic            ring or fused ring system is unsubstituted or substituted on            a carbon or nitrogen atom,        -   wherein            -   R₈ is H, —CH₃, —CF₃, —CH₂OH or —CH₂Cl;            -   R₉ and R₁₀ are each independently H, C₁-C₄alkyl,                C₃-C₇cycloalkyl, —(CH₂)₁₋₆C₃-C₇cycloalkyl,                —(CH₂)₀₋₆phenyl, wherein alkyl, cycloalkyl and phenyl                are unsubstituted or substituted, or            -   R₉ and R₁₀, together with the nitrogen, form het;    -   R₅ is H, C₁-C₁₀alkyl, aryl, phenyl, C₃-C₇cycloalkyl,        —(CH₂)₁₋₆C₃-C₇cycloalkyl, —C₁-C₁₀alkylaryl,        —(CH₂)₀₋₆C₃-C₇cycloalkyl-(CH₂)₀₋₆phenyl,        —(CH₂)₀₋₄CH—((CH₂)₁₋₄phenyl)₂, —(CH₂)₀₋₆CH(phenyl)₂, -indanyl,        —C(O)—C₁-C₁₀alkyl, —C(O)—(CH₂)₁₋₆C₃-C₇-cycloalkyl,        —C(O)—(CH₂)₀₋₆phenyl, —(CH₂)₀₋₆C(O)-phenyl, —(CH₂)₀₋₆het,        —C(O)—(CH₂)₁₋₆het, or    -   R₅ is a residue of an amino acid, wherein the alkyl, cycloalkyl,        phenyl and aryl substituents are unsubstituted or substituted;        and    -   U is as shown in formula (II):

-   -   wherein        -   n is 0-5;        -   X is —CH or N;        -   Ra and Rb are independently an O, S or N atom or CO—C₈alkyl,            wherein one or more of the carbon atoms in the alkyl chain            may be replaced by a heteroatom selected from O, S or N, and            where the alkyl may be unsubstituted or substituted;        -   Rd is selected from:            -   (a) —Re-Q-(Rf)_(p)(Rg)_(q); or            -   (b) Ar₁-D-Ar₂,            -   wherein                -   p and q are independently 0 or 1;                -   Re is C₁-C₈alkyl or alkylidene and                -   Re which may be unsubstituted or substituted;                -   Q is N, O, S, S(O), or S(O)₂;                -   Ar₁ and Ar₂ are substituted or unsubstituted aryl or                    het;                -   Rf and Rg are each independently H, —C₁-C₁₀alkyl,                    C₁-C₁₀alkylaryl, —OH, —O—C₁-C₁₀alkyl,                    —(CH₂)₀₋₆C₃-C₇cycloalkyl, —O—(CH₂)₀₋₆aryl, phenyl,                    aryl, phenyl—phenyl, —(CH₂)₁₋₆het, —O—(CH₂)₁₋₆het,                    —OR₁₁, —C(O)—R₁₁, —C(O)—N(R₁₁)(R₁₂), —N(R₁₁)(R₁₂),                    —S—R₁₁, —S(O)—R₁₁, —S(O)₂—R₁₁, —S(O)₂—NR₁₁R₁₂,                    —N—R₁—S(O)₂—R₁₂, S—C₁-C₁₀alkyl, aryl-C₁-C₄alkyl,                    het-C₁-C₄-alkyl, wherein alkyl, cycloalkyl, het and                    aryl are unsubstituted or substituted,                    —SO₂—C₁-C₂alkyl, —SO₂—C₁-C₂alkylphenyl,                    —O—C₁-C₄alkyl, or                -   Rg and Rf form a ring selected from het or aryl;                -   D is —CO—, —C(O)—C₁-C₇alkylene or arylene, —CF₂—,                    —O—, —S(O)_(r), where r is 0-2, 1,3-dioxolane or                    C₁-C₇alkyl-OH, where alkyl, alkylene or arylene may                    be unsubstituted or substituted with one or more                    halogens, OH; —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃,                    or                -   D is —N(Rh), wherein Rh is H, C₁-C₇alkyl                    (unsubstituted or substituted), aryl,                    —O(C₁-C₇cycloalkyl) (unsubstituted or substituted),                    C(O)—C₁-C₁₀alkyl, C(O)—CO—C₁₀alkyl-aryl;                    C—O—C₁-C₁₀alkyl, C—O—C_(o)-C₁₀alkyl-aryl or                    SO₂—C₁-C₁₀-alkyl, SO₂—(C₁-C₁₀-alkylaryl);        -   Rc is H, or        -   Rc and Rd may together form a cycloalkyl or het, where if Rd            and Rc form a cycloalkyl or het, R₆ is attached to the            formed ring at a C or N atom;        -   R₆, R₇, R₁₆ and R₁₇ are each independently H, —C₁-C₁₀alkyl,            —C₁-C₁₀alkoxy, aryl-C₁-C₁₀alkoxy, —OH, —O—C₁-C₁₀alkyl,            —(CH₂)₀₋₆C₃-C₇cycloalkyl, —O—(CH₂)₀₋₆aryl, phenyl,            —(CH₂)₁₋₆het, —O—(CH₂)₁₋₆het, —OR₁₁, —C(O)—R₁₁,            —C(O)—N(R₁₁)(R₁₂), —N(R₁₁)(R₁₂), —S—R₁₁, —S(O)—R₁₁,            —S(O)₂—R₁₁, —S(O)₂—NR₁₁R₁₂, —NR₁, —S(O)₂—R₁₂, wherein alkyl,            cycloalkyl and aryl are unsubstituted or substituted; and        -   R₆, R₇, R′₆ and R′₇ can be united to form a ring system,        -   wherein            -   R₁₁ and R₁₂ are independently H, C₁-C₁₀alkyl,                —(CH₂)₀₋₆C₃-C₇cycloalkyl, —(CH₂)₀₋₆(CH)₀₋₁(aryl)₁₋₂,                —C(O)—C₁-C₁₀alkyl, —C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl,                —C(O)—O—(CH₂)₀₋₆aryl, —C(O)—(CH₂)₀₋₆O-fluorenyl,                —C(O)—NH—(CH₂)₀₋₆aryl, —C(O)—(CH₂)₀₋₆aryl,                —C(O)—(CH₂)₁₋₆het, —C(S)—C₁-C₁₀alkyl,                —C(S)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(S)—O—(CH₂)₀₋₆aryl,                —C(S)—(CH₂)₀₋₆O-fluorenyl, —C(S)—NH—(CH₂)₀₋₆aryl,                —C(S)—(CH₂)₀₋₆aryl, —C(S)—(CH₂)₁₋₆het, wherein alkyl,                cycloalkyl and aryl are unsubstituted or substituted, or            -   R₁₁ and R₁₂ are a substituent that facilitates transport                of the molecule across a cell membrane, or            -   R₁₁ and R₁₂, together with the nitrogen atom, form het,            -   wherein                -   the alkyl substituents of R₁, and R₁₂ may be                    unsubstituted or substituted by one or more                    substituents selected from C₁-C₁₀alkyl, halogen, OH,                    —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃;                -   substituted cycloalkyl substituents of R₁₁ and R₁₂                    are substituted by one or more substituents selected                    from a C₁-C₁₀alkene, C₁-C₆alkyl, halogen, OH,                    —O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; and                -   substituted phenyl or aryl of R₁₁ and R₁₂ are                    substituted by one or more substituents selected                    from halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,                    nitro, —CN, —O—C(O)—C₁-C₄alkyl and                    —C(O)—O—C₁-C₄aryl;                    or pharmaceutically acceptable salts thereof.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

“Aryl” is an aromatic radical having 6-14 carbon atoms, which may befused or unfused, and which is unsubstituted or substituted by 1 ormore, preferably 1 or 2 substituents, wherein the substituents are asdescribed below. Preferred “aryl” is phenyl, naphthyl or indanyl.

“Het” refers to heteroaryl and heterocyclic rings and fused ringscontaining aromatic and non-aromatic heterocyclic rings. “Het” is a 5-to 7-membered heterocyclic ring containing 14 heteroatoms selected fromN, O and S, or an 8- to 12-membered fused ring system including at leastone 5- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatomsselected from N, O and S. Suitable het substituents includeunsubstituted and substituted pyrrolidyl, tetrahydrofuryl,tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl,morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane,1,4-oxathiapane, furyl, thienyl, pyrrole, pyrazole, triazole,1,2,3-triazole, tetrazolyl, oxadiazole, thiophene, imidazol,pyrrolidine, pyrrolidone, thiazole, oxazole, pyridine, pyrimidine,isoxazolyl, pyrazine, quinoline, isoquinoline, pyridopyrazine,pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran,benzindole, benzoxazole, pyrroloquinoline and the like. The hetsubstituents are unsubstituted or substituted on a carbon atom byhalogen, especially fluorine or chlorine; hydroxy; C₁-C₄alkyl, such asmethyl and ethyl; C₁-C₄alkoxy, especially methoxy and ethoxy; nitro;—O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄alkyl or on a nitrogen by C₁-C₄alkyl,especially methyl or ethyl; —O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄alkyl,such as carbomethoxy or carboethoxy.

When two substituents together with a commonly bound nitrogen are het,it is understood that the resulting heterocyclic ring is anitrogen-containing ring, such as aziridine, azetidine, azole,piperidine, piperazine, morphiline, pyrrole, pyrazole, thiazole,oxazole, pyridine, pyrimidine, isoxazolyl and the like.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorineand chlorine.

Unless otherwise specified “alkyl” includes straight- or branched-chainalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, n-pentyl and branched-pentyl, n-hexyl and branched hexyl andthe like.

A “cycloalkyl” group means C₃-C₁₀cycloalkyl having 3- to 8-ring carbonatoms and may be, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl. Preferably, cycloalkyl iscycloheptyl. The cycloalkyl group may be unsubstituted or substitutedwith any of the substituents defined below, preferably halo, hydroxy orC₁-C₄alkyl, such as methyl.

The amino acid residues include a residue of a standard amino acid, suchas alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine. The amino acid residues also include the sidechains of uncommon and modified amino acids. Uncommon and modified aminoacids are known to those of skill in the art [see, e.g., Fields, Tiamand Barany, Synthetic Peptides A Users Guide, University of WisconsinBiochemistry Center, Chapter 3, (1992)] and include amino acids, such as4-hydroxyproline, 5-hydroxylysine, desmosine, beta (β)-alanine, alpha(α)-, gamma (γ)- and β-aminobutric acid, homocysteine, homoserine,citrulline, ornithine, 2- or 3-amino adipic acid, 6-aminocaproic acid,2- or 3-aminoisobutric acid, 2,3-diaminopropionic acid, diphenylalanine,hydroxyproline and the like. If the side chain of the amino acid residuecontains a derivatizable group, such as COOH, —OH or amino, the sidechain may be derivatized by a substituent that reacts with thederivatizable group. For example, acidic amino acids, like aspartic andglutamic acid, or hydroxy substituted side chains, like those of serineor threonine, may be derivatized to form an ester, or amino side chainsmay form amide or alkylamino derivatives. In particular, the derivativemay be a substituent that facilitates transport across a cell membrane.In addition, any carboxylic acid group in the amino acid residue, e.g.,an α-carboxylic acid group, may be derivatized as discussed above toform an ester or amide.

Substituents that facilitate transport of the molecule across a cellmembrane are known to those of skill in the medicinal chemistry arts.See, e.g., Gangewar et al., Drug Dis Today, Vol. 2, pp. 148-155 (1997);and Bundgaard and Moss, Pharma Res, Vol. 7, p. 885 (1990). Generally,such substituents are lipophilic substituents. Such lipophilicsubstituents include a C₆-C₃₀alkyl, which is saturated, monounsaturated,polyunsaturated, including methylene-interrupted polyene, phenyl, phenylwhich substituted by one or two C₁-C₈alkyl groups, C₅-C₉cycloalkyl,C₅-C₉cycloalkyl, which is substituted by one or two C₁-C₈alkyl groups,-X₁-phenyl, -X₁-phenyl, which is substituted in the phenyl ring by oneor two C₁-C₈alkyl groups, X₁-C₅-C₉cycloalkyl or X₁-C₅-C₉cycloalkyl,which is substituted by one or two C₁-C₈alkyl groups, where X₁ isQ₁-C₂₄alkyl, which is saturated, mono-unsaturated or poly-unsaturatedand straight- or branched-chain.

Unsubstituted is intended to mean that hydrogen is the only substituent.

Any of the above defined aryl, het, alkyl, cycloalkyl, or heterocyclicgroups may be unsubstituted or independently substituted by up to 4,preferably 1, 2 or 3 substituents, selected from the group consistingof: halo, such as Cl or Br; hydroxy; lower alkyl, such as C₁-C₃loweralkyl; lower alkyl, which may be substituted with any of thesubstituents defined herein; lower alkenyl; lower alkynyl; loweralkanoyl; alkoxy, such as methoxy, aryl, such as phenyl or benzyl;substituted aryl, such as fluoro phenyl or methoxy phenyl; amino; mono-or di-substituted amino; amino lower alkyl, such as dimethylamino;acetyl amino; amino lower alkoxy, such as ethoxyamine; nitro; cyano;cyano lower alkyl; carboxy; esterified carboxy, such as lower alkoxycarbonyl, e.g., methoxy carbonyl; n-propoxy carbonyl or iso-propoxycarbonyl; alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-di-substitutedcarbamoyl; carbamates; alkyl carbamic acid esters; amidino; guanidine;urea; ureido; mercapto; sulfo; lower alkylthio; sulfoamino; sulfonamide;benzosulfonamide; sulfonate; sulfanyl lower alkyl, such as methylsulfanyl; sulfoamino; substituted or unsubstituted sulfonamide, such asbenzo sulfonamide; substituted or unsubstituted sulfonate, such aschloro-phenyl sulfonate; lower alkylsulfinyl; phenylsulfinyl;phenyl-lower alkylsulfinyl; alkylphenylsulfinyl; lower alkanesulfonyl;phenylsulfonyl; phenyl-lower alkylsulfonyl; alkylphenylsulfonyl;halogen-lower alkylmercapto; halogen-lower alkylsulfonyl, such asespecially trifluoromethane sulfonyl; phosphono (—P(═O)(OH)₂);hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl;substituted urea, such as 3-trifluoro-methyl-phenyl urea; alkyl carbamicacid ester or carbamates, such as ethyl-N-phenyl-carbamate or —NR₄R₅,

wherein

-   -   R₄ and R₅ can be the same or different and are independently H;        lower alkyl, e.g., methyl, ethyl or propyl, or    -   R₄ and R₅, together with the N atom, form a 3- to 8-membered        heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur        atoms, e.g., piperazinyl, pyrazinyl, lower alkyl-piperazinyl,        pyridyl, indolyl, thiophenyl, thiazolyl, n-methyl piperazinyl,        benzothiophenyl, pyrrolidinyl, piperidino or imidazolinyl, where        the heterocyclic ring may be substituted with any of the        substituents defined herein.

Preferably, the above-mentioned alkyl, cycloalkyl, aryl or het groupsmay be substituted by halogen, carbonyl, thiol, S(O), S(O₂), —OH, —SH,—OCH₃, —SCH₃, —CN, —SCN or nitro.

Where the plural form is used for compounds, salts, pharmaceuticalpreparations, diseases and the like, this is intended to mean also asingle compound, salt or the like.

It will be apparent to one of skill in the art when a compound of theinvention can exist as a salt form, especially as an acid addition saltor a base addition salt. When a compound can exist in a salt form, suchsalt forms are included within the scope of the invention. Although anysalt form may be useful in chemical manipulations, such as purificationprocedures, only pharmaceutically acceptable salts are useful forpharmaceutically products.

Pharmaceutically acceptable salts include, when appropriate,pharmaceutically acceptable base addition salts and acid addition salts,e.g., metal salts, such as alkali and alkaline earth metal salts;ammonium salts; organic amine addition salts; amino acid addition salts;and sulfonate salts. Acid addition salts include inorganic acidaddition, salts such as hydrochloride, sulfate and phosphate; andorganic acid addition salts, such as alkyl sulfonate, arylsulfonate,acetate, maleate, fumarate, tartrate, citrate and lactate. Examples ofmetal salts are alkali metal salts, such as lithium salt, sodium saltand potassium salt; alkaline earth metal salts, such as magnesium saltand calcium salt, aluminum salt and zinc salt. Examples of ammoniumsalts are ammonium salt and tetramethylammonium salt. Examples oforganic amine addition salts are salts with morpholine and piperidine.Examples of amino acid addition salts are salts with glycine,phenylalanine, glutamic acid and lysine. Sulfonate salts includemesylate, tosylate and benzene sulfonic acid salts.

In view of the close relationship between the compounds in free form andthose in the form of their salts, including those salts that can be usedas intermediates, e.g., in the purification or identification of thecompounds, tautomers or tautomeric mixtures and their salts, anyreference to the compounds hereinbefore and hereinafter especially thecompounds of the formula (I), is to be understood as referring also tothe corresponding tautomers of these compounds, especially of compoundsof the formula (I), tautomeric mixtures of these compounds, especiallyof compounds of the formula (I), or salts of any of these, asappropriate and expedient and if not mentioned otherwise.

Any asymmetric carbon atom may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration.Substituents at a ring at atoms with saturated bonds may, if possible,be present in cis(=Z-) or trans(=E-) form. The compounds may thus bepresent as mixtures of isomers or preferably as pure isomers, preferablyas enantiomer-pure diastereomers or pure enantiomers.

Compounds within the scope of formula (I) and the process for theirmanufacture are disclosed in WO 05/097791 published on Oct. 20, 2005,which is hereby incorporated into the present application by reference.A preferred compounds within the scope of formula (I) isN-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamideof formula (III):

Additional compounds that inhibit the binding of the Smac protein toIAPs include compounds of the formula (IV):

wherein

-   -   R₁ is H;    -   R₂ is H, C₁-C₄alkyl, which is unsubstituted or substituted by        one or more substituents selected from halogen, —OH, —SH, —OCH₃,        —SCH₃, —CN, —SCN and nitro;    -   R₃ is H, —CF₃, —C₂F₅, —CH₂-Z, wherein Z is H, —OH, F, Cl, —CH₃,        —CF₃, —CH₂Cl, —CH₂F or —CH₂OH, or    -   R₂ and R₃, together with the nitrogen, form a        C₃-C₆heteroaliphatic ring;    -   R₄ is C₁-C₁₆straight-chain alkyl, C₃-C₁₀branched-chain alkyl,        —(CH₂)₀₋₆C₃-C₇cycloalkyl, —(CH₂)₁₋₆Z₁, —(CH₂)₀₋₆phenyl and        —(CH₂)₀₋₅het, wherein the alkyl, cycloalkyl and phenyl        substituents are unsubstituted or substituted,    -   wherein        -   Z₁ is —N(R₉)—C(O)—C₁-C₁₀alkyl,            —N(R₉)—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl,            —N(R₉)—C(O)—(CH₂)₀₋₆phenyl, —N(R₉)—C(O)—(CH₂)₁₋₆het,            —C(O)—N(R₁₀)(R₁₁), —C(O)—O—C₁-C₁₀alkyl,            —C(O)—O—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆phenyl,            —C(O)—O—(CH₂)₁₋₆het, —O—C(O)—C₁-C₁₀alkyl,            —O—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —O—C(O)—(CH₂)₀₋₆phenyl,            —O—C(O)—(CH₂)₁₋₆het, wherein the alkyl, cycloalkyl and            phenyl substituents are unsubstituted or substituted,        -   wherein            -   R₉ is H; —CH₃, —CF₃, —CH₂OH or CH₂Cl;            -   R₁₀ and R₁₁ are each independently H, C₁-C₄alkyl,                C₃-C₇cycloalkyl, —(CH₂)₁C₃-C₇cycloalkyl,                —(CH₂)₀₋₆phenyl, wherein the alkyl, cycloalkyl and                phenyl substituents are unsubstituted or substituted, or            -   R₁₀ and R₁₁, together with the nitrogen, are het;        -   het is a 5- to 7-membered heterocyclic ring containing 1, 2            or 3 heteroatoms selected from N, O and S, or an 8- to            12-membered fused ring system including at least one 5- to            7-membered heterocyclic ring containing 1, 2 or 3            heteroatoms selected from N, O and S, which heterocyclic            ring or fused ring system is unsubstituted or substituted on            a carbon atom by halogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy,            nitro, —O—C(O)—C₁-C₄alkyl or —C(O)—O—C₁-C₄alkyl or on a            nitrogen by C₁-C₄alkyl, —O—C(O)—C₁-C₄alkyl or            —C(O)—O—C₁-C₄alkyl;    -   X is CH or N;    -   R₅ is H, C₁-C₁₀alkyl-, C₃-C₇cycloalkyl,        —(CH₂)₁₋₆C₃-C₇cycloalkyl, —C₁-C₁₀alkyl-aryl,        —(CH₂)₀₋₆C₃-C₇cycloalkyl-(CH₂)₀₋₆phenyl,        —(CH₂)₀₋₄CH—((CH₂)₁₋₄phenyl)₂, —(CH₂)₀₋₆CH(phenyl)₂,        —C(O)—C₁-C₁₀alkyl, —C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl,        —C(O)—(CH₂)₀₋₆phenyl, —(CH₂)₁₋₆het, —C(O)—(CH₂)₁₋₆het, or    -   R₅ is a residue of an amino acid, wherein the alkyl, cycloalkyl,        phenyl and aryl substituents are unsubstituted or substituted;    -   R₆ is H, methyl, ethyl, —CF₃, —CH₂OH or —CH₂Cl, or    -   R₅ and R₆, together with the nitrogen, are het;    -   R₇ and R₈ are cis relative to the acyl substituent at the one        position of the ring and are each independently H, —C₁-C₁₀alkyl,        —OH, —O—C₁-C₁₀alkyl, —(CH₂)₀₋₆C₃-C₇cycloalkyl, —O—(CH₂)₀₋₆aryl,        phenyl, —(CH₂)₁₋₆het, —O—(CH₂)₁₋₆het, —N(R₁₂)(R₁₃), —S—R₁₂,        —S(O)—R₁₂, —S(O)₂—R₁₂, —S(O)₂—NR₁₂R₁₃, wherein the alkyl,        cycloalkyl and aryl substituents are unsubstituted or        substituted,    -   wherein        -   R₁₂ and R₁₃ are independently H, C₁-C₁₀alkyl,            —(CH₂)₀₋₆C₃-C₇cycloalkyl, —(CH₂)₀₋₆(CH)₀₋₁(aryl)₁₋₂,            —C(O)—C₁-C₁₀alkyl, —C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl,            —C(O)—O—(CH₂)₀₋₆aryl, —C(O)—(CH₂)₀₋₆—O-fluorenyl,            —C(O)—NH—(CH₂)₀₋₆aryl, —C(O)—(CH₂)₀₋₆aryl,            —C(O)—(CH₂)₁₋₆het, wherein the alkyl, cycloalkyl and aryl            substituents are unsubstituted or substituted; or a            substituent that facilitates transport of the molecule            across a cell membrane, or        -   R₁₂ and R₁₃, together with the nitrogen, are het; and        -   aryl is phenyl or naphthyl which is unsubstituted or            substituted;    -   n is 0, 1 or 2;    -   substituted alkyl substituents are substituted by one or more        substituents selected from a double bond, halogen, OH,        —O—C₁-C₆alkyl, —S—C₁-C₆alkyl and —CF₃;    -   substituted cycloalkyl substituents are substituted by one or        more substituents selected from a double bond, C₁-C₆alkyl,        halogen, OH, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl and —CF₃; and    -   substituted phenyl or aryl are substituted by one or more        substituents selected from halogen, hydroxy, C₁-C₄alkyl,        C₁-C₄alkoxy, nitro, —CN, —O—C(O)—C₁-C₄alkyl and        —C(O)—O—C₁-C₄alkyl.

Unsubstituted is intended to mean that hydrogen is the only substituent.

Halogen is fluorine, chlorine, bromine or iodine, especially fluorineand chlorine.

Unless otherwise specified alkyl substituents include straight- orbranched-chain alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyland branched hexyl and the like.

Cycloalkyl substituents include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

Compounds within the scope of formula (VIII) and the process for theirmanufacture are disclosed in WO 04/005284, which is hereby incorporatedinto the present application by reference.

In each case where citations of patent applications are given above, thesubject matter relating to the compounds is hereby incorporated into thepresent application by reference. Comprised are likewise thepharmaceutically acceptable salts thereof, the corresponding racemates,diastereoisomers, enantiomers, tautomers, as well as the correspondingcrystal modifications of above disclosed compounds where present, e.g.,solvates, hydrates and polymorphs, which are disclosed therein. Thecompounds used as active ingredients in the combinations of theinvention can be prepared and administered as described in the citeddocuments, respectively. Also within the scope of this invention is thecombination of more than two separate active ingredients as set forthabove, i.e., a pharmaceutical combination within the scope of thisinvention could include three active ingredients or more.

In accordance with the particular findings of the present invention,there is provided:

1. A pharmaceutical combination comprising:

-   -   a) a compound that inhibit the binding of the Smac protein to        IAPs of formula (I) or (IV); and    -   b) at least one taxane.        2. A method for treating or preventing proliferative disease in        a subject in need thereof, comprising co-administration to said        subject, e.g., concomitantly or in sequence, of a        therapeutically effective amount of a compound that inhibit the        binding of the Smac protein to IAP's of formula (I) or (VIII)        and a taxane. Examples of proliferative diseases include, e.g.,        tumors, leukemias and myelomas.        3. A pharmaceutical combination as defined under 1) above, e.g.        for use in a method as defined under 2) above.        4. A pharmaceutical combination as defined under 1) above for        use in the preparation of a medicament for use in a method as        defined under 2) above.

Utility of the combination of the invention in a method as hereinabovespecified, may be demonstrated in animal test methods, as well as inclinic, e.g., in accordance with the methods hereinafter described.

It has now surprisingly been found that the combination of a compoundsthat inhibit the binding of the Smac protein to IAPs and a taxanepossesses therapeutic properties, which render it particularly useful asa treatment for proliferative diseases.

In another embodiment, the instant invention provides a method fortreating proliferative diseases comprising administering to a mammal inneed of such treatment a therapeutically effective amount of thecombination of compounds that inhibit the binding of the Smac protein toIAPs and a taxane or pharmaceutically acceptable salts or prodrugsthereof.

In another embodiment, compounds that inhibit the binding of the Smacprotein to IAPs are selected from compounds of formulae (I) and (IV) asdefined above.

Preferably, the instant invention provides a method for treatingmammals, especially humans, suffering from proliferative diseasescomprising administering to a mammal in need of such treatment aninhibiting amount of the combination of compounds that inhibit thebinding of the Smac protein to IAPs and a taxane or pharmaceuticallyacceptable salts thereof.

In the present description, the term “treatment” includes bothprophylactic or preventative treatment, as well as curative or diseasesuppressive treatment, including treatment of patients at risk ofcontracting the disease or suspected to have contracted the disease, aswell as ill patients. This term further includes the treatment for thedelay of progression of the disease.

The term “curative:, as used herein, means efficacy in treating ongoingepisodes involving proliferative diseases.

The term “prophylactic” means the prevention of the onset or recurrenceof diseases involving proliferative diseases.

The term “delay of progression”, as used herein, means administration ofthe active compound to patients being in a pre-stage or in an earlyphase of the disease to be treated, in which patients, e.g. a pre-formof the corresponding disease is diagnosed or which patients are in acondition, e.g., during a medical treatment or a condition resultingfrom an accident, under which it is likely that a corresponding diseasewill develop.

This unforeseeable range of properties means that the use of thecombination of a compounds that inhibit the binding of the Smac proteinto IAPs and taxanes are of particular interest for the manufacture of amedicament for the treatment of proliferative diseases.

To demonstrate that the combination of a compounds that inhibit thebinding of the Smac protein to IAPs and taxanes is particularly suitablefor the treatment of proliferative diseases with good therapeutic marginand other advantages, clinical trials can be carried out in a mannerknown to the skilled person.

A. Combined Treatment

A combination which comprises:

-   -   (a) a taxane; and    -   (b) an IAP inhibitor, in which the active ingredients are        present in each case in free form or in the form of a        pharmaceutically acceptable salt; and, optionally, at least one        pharmaceutically acceptable carrier,        will be referred to hereinafter as a COMBINATION OF THE        INVENTION.

Suitable clinical studies are, e.g., open-label, dose escalation studiesin patients with proliferative diseases. Such studies prove inparticular the synergism of the active ingredients of the COMBINATION OFTHE INVENTION. The beneficial effects can be determined directly throughthe results of these studies which are known as such to a person skilledin the art. Such studies are, in particular, suitable to compare theeffects of a monotherapy using the active ingredients and a COMBINATIONOF THE INVENTION. Preferably, the dose of:

-   -   agent (a) is escalated until the Maximum Tolerated Dosage is        reached; and    -   agent (b) is administered with a fixed dose.

Alternatively, the agent (a) is administered in a fixed dose and thedose of agent (b) is escalated. Each patient receives doses of the agent(a) either daily or intermittent. The efficacy of the treatment can bedetermined in such studies, e.g., after 12, 18 or 24 weeks by evaluationof symptom scores every 6 weeks.

The administration of a pharmaceutical COMBINATION OF THE INVENTIONresults not only in a beneficial effect, e.g., a synergistic therapeuticeffect, e.g., with regard to alleviating, delaying progression of orinhibiting the symptoms, but also in further surprising beneficialeffects, e.g., fewer side effects, an improved quality of life or adecreased morbidity, compared with a monotherapy applying only one ofthe pharmaceutically active ingredients used in the combination of theinvention.

A further benefit is that lower doses of the active ingredients of theCOMBINATION OF THE INVENTION can be used, e.g., that the dosages neednot only often be smaller but are also applied less frequently, whichmay diminish the incidence or severity of side effects. This is inaccordance with the desires and requirements of the patients to betreated.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

It is one objective of this invention to provide a pharmaceuticalcomposition comprising a quantity, which is jointly therapeuticallyeffective at targeting or preventing proliferative diseases aCOMBINATION OF THE INVENTION. In this composition, agents (a) and (b)may be administered together, one after the other or separately in onecombined unit dosage form or in two separate unit dosage forms. The unitdosage form may also be a fixed combination.

The pharmaceutical compositions for separate administration of agents(a) and (b) or for the administration in a fixed combination, i.e., asingle galenical composition comprising at least two combinationpartners (a) and (b), according to the invention may be prepared in amanner known per se and are those suitable for enteral, such as oral orrectal, and parenteral administration to mammals (warm-blooded animals),including humans, comprising a therapeutically effective amount of atleast one pharmacologically active combination partner alone, e.g., asindicated above, or in combination with one or more pharmaceuticallyacceptable carriers or diluents, especially suitable for enteral orparenteral application.

Suitable pharmaceutical compositions contain, for example, from about0.1% to about 99.9%, preferably from about 1% to about 60%, of theactive ingredient(s). Pharmaceutical preparations for the combinationtherapy for enteral or parenteral administration are, e.g., those inunit dosage forms, such as sugar-coated tablets, tablets, capsules orsuppositories, or ampoules. If not indicated otherwise, these areprepared in a manner known per se, e.g., by means of conventionalmixing, granulating, sugar-coating, dissolving or lyophilizingprocesses. It will be appreciated that the unit content of a combinationpartner contained in an individual dose of each dosage form need not initself constitute an effective amount since the necessary effectiveamount can be reached by administration of a plurality of dosage units.

In particular, a therapeutically effective amount of each of thecombination partner of the combination of the invention may beadministered simultaneously or sequentially and in any order, and thecomponents may be administered separately or as a fixed combination. Forexample, the method of preventing or treating proliferative diseasesaccording to the invention may comprise:

-   -   (i) administration of the first agent (a) in free or        pharmaceutically acceptable salt form; and    -   (ii) administration of an agent (b) in free or pharmaceutically        acceptable salt form,        simultaneously or sequentially in any order, in jointly        therapeutically effective amounts, preferably in synergistically        effective amounts, e.g., in daily or intermittently dosages        corresponding to the amounts described herein. The individual        combination partners of the combination of the invention may be        administered separately at different times during the course of        therapy or concurrently in divided or single combination forms.        Furthermore, the term administering also encompasses the use of        a pro-drug of a combination partner that convert in vivo to the        combination partner as such. The instant invention is therefore        to be understood as embracing all such regimens of simultaneous        or alternating treatment and the term “administering” is to be        interpreted accordingly.

The term “a combined preparation”, as used herein, defines especially a“kit of parts” in the sense that the combination partners (a) and (b) asdefined above can be dosed independently or by use of different fixedcombinations with distinguished amounts of the combination partners (a)and (b), i.e., simultaneously or at different time points. The parts ofthe kit of parts can then, e.g., be administered simultaneously orchronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts. Theratio of the total amounts of the combination partner (a) to thecombination partner (b) to be administered in the combined preparationcan be varied, e.g., in order to cope with the needs of a patientsub-population to be treated or the needs of the single.

The effective dosage of each of the combination partners employed in thecombination of the invention may vary depending on the particularcompound or pharmaceutical composition employed, the mode ofadministration, the condition being treated, the severity of thecondition being treated. Thus, the dosage regimen of the combination ofthe invention is selected in accordance with a variety of factorsincluding the route of administration and the renal and hepatic functionof the patient. A clinician or physician of ordinary skill can readilydetermine and prescribe the effective amount of the single activeingredients required to alleviate, counter or arrest the progress of thecondition. Optimal precision in achieving concentration of the activeingredients within the range that yields efficacy without toxicityrequires a regimen based on the kinetics of the active ingredients'availability to target sites.

Daily dosages for agent (a) or (b) or will, of course, vary depending ona variety of factors, for example the compound chosen, the particularcondition to be treated and the desired effect. In general, however,satisfactory results are achieved on administration of agent (a) atdaily dosage rates of the order of ca. 0.03-5 mg/kg/day, particularly0.1-5 mg/kg/day, e.g., 0.1-2.5 mg/kg/day, as a single dose or in divideddoses. Agents (a) and (b) may be administered by any conventional route,in particular, enterally, e.g., orally, e.g., in the form of tablets,capsules, drink solutions or parenterally, e.g., in the form ofinjectable solutions or suspensions. Suitable unit dosage forms for oraladministration comprise from ca. 0.02-50 mg active ingredient, usually0.1-30 mg, e.g., agent (a) or (b), together with one or morepharmaceutically acceptable diluents or carriers therefore.

Agent (b) may be administered to a human in a daily dosage range of0.5-1000 mg. Suitable unit dosage forms for oral administration comprisefrom ca. 0.1-500 mg active ingredient, together with one or morepharmaceutically acceptable diluents or carriers therefore.

The administration of a pharmaceutical combination of the inventionresults not only in a beneficial effect, e.g., a synergistic therapeuticeffect, e.g., with regard to inhibiting the unregulated proliferation ofhaematological stem cells or slowing down the progression of leukemias,such as chronic myeloid leukemia (CML), acute lymphocyte leukemia (ALL)or acute myeloid leukemia (AML), or the growth of tumors, but also infurther surprising beneficial effects, e.g., less side effects, animproved quality of life or a decreased morbidity, compared to amonotherapy applying only one of the pharmaceutically active ingredientsused in the combination of the invention.

A further benefit is that lower doses of the active ingredients of thecombination of the invention can be used, e.g., that the dosages neednot only often be smaller but are also applied less frequently, or canbe used in order to diminish the incidence of side effects. This is inaccordance with the desires and requirements of the patients to betreated.

Combinations of compounds that inhibit the binding of the Smac proteinto IAPs and taxanes may be combined, independently or together, with oneor more pharmaceutically acceptable carriers and, optionally, one ormore other conventional pharmaceutical adjuvants and administeredenterally, e.g., orally, in the form of tablets, capsules, caplets, etc.or parenterally, e.g., intraperitoneally or intravenously, in the formof sterile injectable solutions or suspensions. The enteral andparenteral compositions may be prepared by conventional means.

The combination of compounds that inhibit the binding of the Smacprotein to IAPs and taxanes can be used alone or combined with at leastone other pharmaceutically active compound for use in these pathologies.These active compounds can be combined in the same pharmaceuticalpreparation or in the form of combined preparations “kit of parts” inthe sense that the combination partners can be dosed independently or byuse of different fixed combinations with distinguished amounts of thecombination partners, i.e., simultaneously or at different time points.The parts of the kit of parts can then, e.g., be administeredsimultaneously or chronologically staggered, that is at different timepoints and with equal or different time intervals for any part of thekit of parts. Non-limiting examples of compounds which can be cited foruse in combination with the combination of a compounds that inhibit thebinding of the Smac protein to IAPs and taxanes are cytotoxicchemotherapy drugs, such as cytosine arabinoside, daunorubicin,doxorubicin, cyclophosphamide, VP-16, or imatinib etc. Further, thecombination of a compounds that inhibit the binding of the Smac proteinto IAPs and taxanes could be combined with other inhibitors of signaltransduction or other oncogene-targeted drugs with the expectation thatsignificant synergy would result.

The COMBINATION OF THE INVENTION can be a combined preparation or apharmaceutical composition.

Moreover, the present invention relates to a method of treating awarm-blooded animal having a proliferative disease comprisingadministering to the animal a COMBINATION OF THE INVENTION in a quantitywhich is therapeutically effective against said proliferative disease.

Furthermore, the present invention pertains to the use of a COMBINATIONOF THE INVENTION for the treatment of a proliferative disease and forthe preparation of a medicament for the treatment of a proliferativedisease.

Moreover, the present invention provides a commercial package comprisingas active ingredients COMBINATION OF THE INVENTION, together withinstructions for simultaneous, separate or sequential use thereof in thedelay of progression or treatment of a proliferative disease.

Preferred embodiments of the invention are represented by combinationscomprising:

-   -   compound I and paclitaxel;    -   compound IV and paclitaxel;    -   compound I and docetaxel; and

compound IV and docetaxel.

In further aspects, the present inventions provides:

-   -   a combination which comprises:    -   (a) a COMBINATION OF THE INVENTION, wherein the active        ingredients are present in each case in free form or in the form        of a pharmaceutically acceptable salt or any hydrate thereof;        and, optionally,    -   (b) at least one pharmaceutically acceptable carrier; for        simultaneous, separate or sequential use;    -   a pharmaceutical composition comprising:    -   (a) a quantity which is jointly therapeutically effective        against a proliferative disease of a COMBINATION OF THE        INVENTION; and    -   (b) at least one pharmaceutically acceptable carrier;    -   the use of a COMBINATION OF THE INVENTION for the treatment of a        proliferative disease;    -   the use of a COMBINATION OF THE INVENTION for the preparation of        a medicament for the treatment of a proliferative disease;    -   the use of a COMBINATION OF THE INVENTION wherein the compound        that inhibit the binding of the Smac protein to IAPs is a        compound of formula (I); and    -   the use of COMBINATION OF THE INVENTION wherein the compound        that inhibit the binding of the Smac protein to IAPs is a        compound of formula (IV).

In particular, the present invention relates to a combinationcomprising:

-   -   (a) a taxane; and    -   (b) a compound that inhibit the binding of the Smac protein to        IAPs.

Moreover, in particular, the present invention relates to a combinedpreparation, which comprises:

-   -   (a) one or more unit dosage forms of a taxane; and    -   (b) one or more unit dosage forms of a compound that inhibit the        binding of the Smac protein to IAPs:

Furthermore, in particular, the present invention pertains to the use ofa combination comprising:

-   -   (a) a taxane; and    -   (b) a compound that inhibit the binding of the Smac protein to        IAPs for the preparation of a medicament for the treatment of a        proliferative disease.

B. Diseases to be Treated

The term “proliferative disease” includes but is not restricted totumors, psoriasis, restenosis, sclerodermitis and fibrosis.

The term hematological malignancy, refers in particular to leukemias,especially those expressing Bcr-Abl, c-Kit or HDAC (or those dependingon Bcr-Abl, c-Kit or HDAC) and includes, but is not limited to, CML andALL, especially the Philadelphia chromosome positive acute lymphocyteleukemia (Ph+ALL), as well as Imatinib-resistant leukemia. Especiallypreferred is use of the combinations of the present invention forleukemias, such as CML, ALL or AML. Most especially preferred is use indiseases which show resistance to Imatinib and is sold under the nameGleevec®.

The term “a solid tumor disease” especially means ovarian cancer, breastcancer, cancer of the colon and generally the gastrointestinal tract,cervix cancer, lung cancer, e.g., small-cell lung cancer andnon-small-cell lung cancer, head and neck cancer, bladder cancer, cancerof the prostate or Kaposi's sarcoma.

The combinations according to the invention, that inhibit the proteinkinase activities mentioned, especially tyrosine protein kinasesmentioned above and below, can therefore be used in the treatment ofprotein kinase dependent diseases. Protein kinase dependent diseases areespecially proliferative diseases, preferably benign or especiallymalignant tumours, e.g., carcinoma of the kidneys, brain, liver, adrenalglands, bladder; breast, stomach (especially gastric tumors), ovaries,colon, rectum, prostate, pancreas, lungs (especially SCLC), vagina orthyroid, sarcoma, multiple myeloma, glioblastomas and numerous tumoursof the neck and head, as well as leukemias; especially colon carcinomaor colorectal adenoma, or a tumor of the neck and head, an epidermalhyperproliferation, especially psoriasis, prostate hyperplasia, aneoplasia, especially of epithelial character, preferably mammarycarcinoma, or a leukemia. They are able to bring about the regression oftumours and to prevent the formation of tumour metastases and the growthof (also micro) metastases. In addition they can be used in epidermalhyperproliferation, e.g., psoriasis; in prostate hyperplasia; and in thetreatment of neoplasias, especially of epithelial character, e.g.,mammary carcinoma. It is also possible to use the combinations of thepresent invention in the treatment of diseases of the immune systeminsofar as several or, especially, individual tyrosine protein kinasesare involved; furthermore, the combinations of the present invention canbe used also in the treatment of diseases of the central or peripheralnervous system where signal transmission by at least one tyrosineprotein kinase, especially selected from those mentioned specifically,is involved.

In CML, a reciprocally balanced chromosomal translocation inhematopoietic stem cells (HSCs) produces the Bcr-Abl hybrid gene. Thelatter encodes the oncogenic Bcr-Abl fusion protein. Whereas Abl encodesa tightly regulated protein tyrosine kinase, which plays a fundamentalrole in regulating cell proliferation, adherence and apoptosis, theBcr-Abl fusion gene encodes as, constitutively activated kinase, whichtransforms HSCs to produce a phenotype exhibiting deregulated clonalproliferation, reduced capacity to adhere to the bone marrow stroma anda reduces apoptotic response to mutagenic stimuli, which enable it toaccumulate progressively more malignant transformations. The resultinggranulocytes fail to develop into mature lymphocytes and are releasedinto the circulation, leading to a deficiency in the mature cells andincreased susceptibility to infection. ATP-competitive inhibitors ofBcr-Abl have been described which prevent the kinase from activatingmitogenic and anti-apoptotic pathways (e.g., P-3 kinase and STAT5),leading to the death of the Bcr-Abl phenotype cells and therebyproviding an effective therapy against CML. The combinations of thepresent invention are thus especially appropriate for the therapy ofdiseases related to its overexpression, especially leukemias, such asleukemias, e.g., CML or ALL.

In a broader sense of the invention, a proliferative disease includeshyperproliferative conditions, such as leukemias, hyperplasias, fibrosis(especially pulmonary, but also other types of fibrosis, such as renalfibrosis), angiogenesis, psoriasis, atherosclerosis; and smooth muscleproliferation in the blood vessels, such as stenosis or restenosisfollowing angioplasty. In another aspect the combinations of the presentinvention could be used to treat arthritis.

Combinations of the present invention can also be used to treat orprevent fibrogenic disorders, such as scleroderma (systemic sclerosis);diseases associated with protein aggregation and amyloid formation, suchas Huntington's disease; inhibition of the replication of hepatitis Cvirus and treating hepatitis C virus; treating tumors associated withviral infection, such as human papilloma virus; and inhibiting virusesdependent of heat-shock proteins.

The combinations of the present invention primarily inhibit the growthof blood vessels and are thus, e.g., effective against a number ofdiseases associated with deregulated angiogenesis, especially diseasescaused by ocular neovascularisation, especially retinopathies, such asdiabetic retinopathy or age-related macula degeneration; psoriasis;haemangioblastoma, such as haemangioma; mesangial cell proliferativedisorders, such as chronic or acute renal diseases, e.g., diabeticnephropathy; malignant nephrosclerosis; thrombotic microangiopathysyndromes or transplant rejection; or especially inflammatory renaldisease, such as glomerulonephritis, especially mesangioproliferativeglomerulonephritis; haemolytic-uraemic syndrome; diabetic nephropathy;hypertensive nephrosclerosis; atheroma; arterial restenosis; autoimmunediseases; diabetes; endometriosis; chronic asthma; and especiallyneoplastic diseases (solid tumors, but also leukemias and otherhaematological malignancies), such as especially breast cancer, cancerof the colon, lung cancer (especially small-cell lung cancer), cancer ofthe prostate or Kaposi's sarcoma. Combinations of the present inventioninhibit the growth of tumors and are especially suited to preventing themetastatic spread of tumors and the growth of micrometastases.

Combinations of the present invention may in particular be used totreat:

-   -   (i) a breast tumor; an epidermoid tumor, such as an epidermoid        head and/or neck tumor or a mouth tumor; a lung tumor, e.g., a        small cell or non-small cell lung tumor; a gastrointestinal        tumor, e.g., a colorectal tumor; or a genitourinary tumor, e.g.,        a prostate tumor, especially a hormone-refractory prostate        tumor;    -   (ii) a proliferative disease that is refractory to the treatment        with other chemotherapeutics; or    -   (iii) a tumor that is refractory to treatment with other        chemotherapeutics due to multi-drug resistance.

EXAMPLE 1

The combination of Docetaxel with a compound of formula (III) in theovarian carcinoma line SKOV3 results in significant synergy in vitro.FIG. 1 indicates anti-proliferative activity of compound of formula(III) alone (bottom row), Docetaxel alone (most leftward column) andcombinations of the two agents across a dose range.

FIG. 2 is the corresponding isobologram at 70% growth inhibition.

EXAMPLE 2

The combination of a compound of formula (III) and Paclitaxel hassuperior anti-tumor activity compared to either agent administered as asingle agent in the orthotopic breast cancer model MDA-MB-231.Established tumors were treated for two weeks with the dose regimensindicated in FIG. 2.

EXAMPLE 3

FIG. 4 indicates anti-proliferative activity of Taxol is dramaticallyenhanced by combination with a compound of formula (III in the melanomacell line A375. Top curve shows dose response of Taxol alone in A375 inthree day proliferation assay. Bottom two curves show Taxol doseresponse in presence of either 6 μM or 12 μM compound of formula (III).

The compound of formula (III) has no stand alone activity in A375 (datanot shown).

EXAMPLE 4

IAP Inhibitor compounds such as LBW242 display single agent activity ona limited number of tumor cell lines in vitro. To determine whether alarger number of cell lines are responsive to an IAP Inhibitor incombination with Taxol, Taxol dose response evaluations are performed inthe presence or absence of LBW242 with 10-12 tumor cell linesrepresenting the following cancers: lung, ovarian, melanoma, pancreatic.The criteria used for an assignment of combination activity—eitheradditivity or synergy—is a minimum of a five fold potency shift for theIC₅₀ of Taxol in combination with LBW242 relative to Taxol alone. Tumorcell lines which are responsive to LBW242 as, a monotherapy such asMDA231 and SKOV3 also exhibit combination activity with Taxol. In allcancer types tested, tumor cell lines are identified in which the IAPInhibitor compound has no single agent activity yet enhances theresponse to Taxol. Thus, the range of tumor cell lines sensitive toLBW242 in combination with a cytotoxic agent is slightly larger than therange responsive as a single agent.

LBW242, LCJ917, LCP656 and LCL161 are Smac mimetic small molecules withnM affinity for the BIR3 domain of XIAP and CIAP1. As Inhibitor ofApoptosis Proteins (IAPs) are thought to protect tumor cells fromapoptotic cell death, it was anticipated that such agents wouldsensitize tumor cells to apoptotic stimuli. Interestingly, such agentshave anti-proliferative/apoptosis inducing activity as single agentsagainst a narrow range of tumor cell lines for reasons which remainunclear. To determine whether the spectrum of tumor cell lines whichresponded to these agents would be wider in combination with thecytotoxic drug Taxol, we subject panels of tumor cell lines representinga number of human cancers to in vitro combination analyses.

Materials and Methods

MTS Reagent (#G1111; Promega) in PBS, pH 6-6.5. Phenazine Methosulfate(PMS) (#P-5812; Sigma). 96 well tissue culture plates (#3585; CorningCostar). RPMI 1640 cell culture medium (#22400-071; Invitrogen).Penicillin/Streptomycin (#15140-122; Invitrogen). Fetal Bovine Serum(#10082-139; Invitrogen). (Note: RPMI 1640+10%FBS+Penicillin/Streptomycin is “RPMI/10% FBS Complete medium”). 0.25%Trypsin-EDTA (#25200-056; Invitrogen). The IAP Inhibitor compoundsLBW242, LCJ917, LCP656 and LCL161 are dissolved in DMSO at aconcentration of 10 mM and stored at −20° C. Tumor Cell Lines arepurchased from ATCC.

MTS Assay

Cell proliferation/cell death is analyzed in 72 hr.3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt (MTS) assays. Tumor cell lines are plated at subconfluentdensities in 96 well plate format and allowed to adhere for 12-16 hr.Cpds are then added according to the following schemes: i.Chemotherapeutic agents or cytotoxic cpds (Ctx) are added alone, in an8-point/10-fold titration scheme from high to low dose, in triplicate.ii. IAP-inhibitor (NVP-LBW242) is added alone, at a single fixed dose(dose determined in stand alone MTS assays) in triplicate. iii. Ctxagent (8-point/1-fold scheme) and LBW242 (single fixed dose) are addedtogether, simultaneously, in triplicate. Once all dosing is completed,cells are cultured for a further 72 hr. and then assayed using the MTSformat:

Day −1

-   1. Plate cells in RPMI/10% FBS Complete medium. Set-up Time 0 (T.0)    and Experimental (EXP) plates as appropriate for each cell line.    Each plate will contain culture medium (CM) alone (Blank) wells (200    ul/well).-   2. An additional “Blank” plate will contain Blank wells: the center    24 wells will contain 12 wells with 100 ul CM/well and 12 wells with    110 ul CM/well. All surrounding wells will contain 200 ul CM/well.-   3. Trypsinize cells at 37° c./5% CO₂ for up to 5′, quench the    trypsin with CM and then plate cells onto 96 well plates at 90    ul/well. Seed cells at densities appropriate for each cell line    (appropriate cell densities will yield optimal cell growth which is    reflected in T.0D 490 values between 0.3-0.8). Add 90 ul CM to 6    Blank wells on the T.0 plate and 200 ul CM to all surrounding wells.    Add 200 ul CM to all outer wells on Exp plates. Culture plates @ 37°    C./5% CO2 for 24 (T.0 plate) to 96 hr. (EXP plates).

Day 0

1. Add MTS/PMS reagents to T.0 Plate(s). Mix enough of each reagent (100ul 500 uM PMS per 2 ml 333 ug/ml MTS reagent/96 well plate) for 20ul/well. Add 20 ul mixture to ea. well & incubate plate(s) 2 hr. @ 37°C./5% CO2. Read OD 490 nm using SoftMax Pro software on a MolecularDevices (Sunnyvale, Calif.) Spectrophotometer. Calculate T.0 values foreach cell line to be assayed by generating the mean value of the OD 490nm readings from each cell line's T.0 wells (6/cell line) andsubtracting the mean OD 490 nm values from Blank wells.2. Dose EXP plate(s) with appropriate Cdps in triplicate in the schemesshown in FIG. 5. Incubate plates at 37° C./5% CO2 for 72 hr.

Day 3

1. Add MTS/PMS reagents to EXP Plate(s). Mix enough of each reagent (100ul 500 uM PMS per 2 ml 333 ug/ml MTS reagent/96 well plate) for 20ul/well. Add 20 ul mixture to ea. well & incubate plate(s) 2 hr. @ 37°C./5% CO2. Read OD 490 nm using SoftMax Pro software on a MolecularDevices Spectrophotometer. MTS Data is generated as described below:

Calculate % CG by first averaging triplicate results (subtracting blankmedium values) as follows:

If OD treated>OD T.0, then: % CG=100×[(OD treated−OD T.0)/(OD 72 hr.untreated−OD T.0)]

If OD treated<OD T.0, then: % CG=100×[(OD treated−OD T.0)/OD T.0]

Selection of IAP Inhibitor Dose Levels

IAP Inhibitors are used at a single fixed dose of 10 uM (12 uM inearliest assays) in lines where compound shows no effect (IC₅₀>10 uM) asa single agent.

IAP Inhibitors are used at a single fixed dose yielding 70-80% controlcell growth (% CG) (between IC20-IC30 dose) in lines where compoundsshow moderate stand alone activity (IC50 1-10 uM) as a single agent.

In most cases, fixed doses in specific cell lines are set by generatingempirical data in MTS assays.

Criteria for Call of Combination Activity

Combinations exhibiting a ≧5-fold potency shift in the IC50 dose ascompared with Taxol alone are scored as a combination activity hitsprovided that under similar conditions LBW242 by itself did not resultin <70% CG (IC30).

True assessment of synergy requires fixed ratio titrations ofcombination partners and determination of combination indices. The abovecriteria do not formally distinguish between synergy and additivity.

Ovarian Tumor Cell Lines:

FIG. 5 Taxol+100 nMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in OVCAR-4

FIG. 6 Taxol+1 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in OVCAR-4

FIG. 7 Taxol+10 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombinations in TOV 21G

FIG. 8 Taxol+80 nMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombinations in SKOV-3

Melanoma Cancer Cell Lines:

FIG. 9 Taxol+10 uMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in SKMEL-2

FIG. 10 Taxol+10 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in SKMEL-2

FIG. 11 Taxol+10 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in MEWO

FIG. 12 Taxol+10 uMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in A375

FIG. 13 Taxol+1 uMN-[1-Cyclohexyl-2-(2-{2-[(4-fluoro-phenyl)-methyl-amino]-pyridin-4-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamideCombination in A375

FIG. 14 Taxol+6 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in A375

FIG. 15 Taxol+10 uMN-(1-Cyclohexyl-2-{2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in A375

FIG. 16 Taxol+10 uMN-(1′-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in A375

FIG. 17 Taxol+1 uMN-[1-Cyclohexyl-2-(2-{2-[(4-fluoro-phenyl)-methyl-amino]-pyridin-4-yl}pyrrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamideCombination in A375

FIG. 18 Taxol+10 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in A375

FIG. 19 Taxol+10 uMN-(1-Cyclohexyl-2-{2-[5-(4-fluoro-phenoxy)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in A375

Lung Tumor Cell Lines:

FIG. 20 Taxol+10 uMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in NCl—H2030

FIG. 21 Taxol+2 uMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in NCl—H23

FIG. 22 Taxol+0.5 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in SK-LU-1

FIG. 23 Taxol+7 uMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in NCl—H441

FIG. 24Taxol+N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in NCl—H441

FIG. 25 Taxol+4 uMN-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideCombination in A427

FIG. 26 Taxol+, 10 uMN-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl)-ethyl]-2-methylamino-propionamideCombination in A427

1. A pharmaceutical combination comprising: (a) a compound that inhibitthe binding of the Smac protein to Inhibitor of Apoptosis Proteins(IAPs) of formula (I)

wherein R₁ is H, C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkynyl orC₃-C₁₀cycloalkyl, which are unsubstituted or substituted; R₂ is H,C₁-C₄alkyl, C₁-C₄alkenyl, C₁-C₄alkynyl or C₃-C₁₀cycloalkyl, which areunsubstituted or substituted; R₃ is H, —CF₃, —C₂F₅, C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkynyl, —CH₂-Z, wherein Z is H, —OH, F, Cl,—CH₃—CF₃, —CH₂Cl, —CH₂F or —CH₂OH, or R₂ and R₃, together with thenitrogen, form a het ring; R₄ is C₁-C₁₆straight- or branched-alkyl,C₁-C₁₆alkenyl, C₁-C₁₆alkynyl or —C₃-C₁₀cycloalkyl, —(CH₂)₁₋₆Z₁,—(CH₂)₀₋₆aryl and —(CH₂)₀₋₆het, wherein alkyl, cycloalkyl and phenyl areunsubstituted or substituted, wherein Z₁ is —N(R₈)—C(O)—C₁-C₁₀alkyl,—N(R₈)—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —N(R₈)—C(O)—(CH₂)₀₋₆phenyl,—N(R₈)—C(O)—(CH₂)₁₋₆het, —C(O)—N(R₉)(R₁₀), —C(O)—O—C₁-C₁₀alkyl,—C(O)—O—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆phenyl,—C(O)—O—(CH₂)₁₋₆het, —O—C(O)C₁-C₁₀alkyl,—O—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —O—C(O)—(CH₂)₀₋₆phenyl,—O—C(O)—(CH₂)₁₋₆het, wherein alkyl, cycloalkyl and phenyl areunsubstituted or substituted; and het is a 5 to 7-membered heterocyclicring containing 14 heteroatoms selected from N, O and S, or an 8- to12-membered fused ring system including at least one 5- to 7-memberedheterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O,and S, which heterocyclic ring or fused ring system is unsubstituted orsubstituted on a carbon or nitrogen atom, wherein R₈ is H, —CH₃, —CF₃,—CH₂OH or —CH₂Cl; R₉ and R₁₀ are each independently H, C₁-C₄alkyl,C₃-C₇cycloalkyl, —(CH₂)₁₋₆C₃-C₇cycloalkyl, —(CH₂)₀₋₆phenyl, whereinalkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R₉,and R₁₀, together with the nitrogen, form het; R₅ is H, C₁-C₁₀alkyl,aryl, phenyl, C₃-C₇cycloalkyl, —(CH₂)₁₋₆C₃-C₇cycloalkyl,—C₁-C₁₀alkyl-aryl, —(CH₂)₀₋₆C₃-C₇cycloalkyl-(CH₂)₀₋₄phenyl,—(CH₂)₀₋₄CH—((CH₂)₁₋₄phenyl)₂, —(CH₂)₀₋₆CH(phenyl)₂, -indanyl,—C(O)—C₁-C₁₀alkyl, —C(O)—(CH₂)₁₋₆C₃-C₇-cycloalkyl, —C(O)—(CH₂)₀₋₆phenyl,—(CH₂)₀₋₆C(O)-phenyl, —(CH₂)₀₋₆het, —C(O)—(CH₂)₁₋₆het, or R₅ is aresidue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and arylsubstituents are unsubstituted or substituted; and U is as shown informula (II):

wherein n is 0-5; X is —CH or N; Ra and Rb are independently an O, S orN atom or C₀-C₈alkyl, wherein one or more of the carbon atoms in thealkyl chain may be replaced by a heteroatom selected from O, S or N, andwhere the alkyl may be unsubstituted or substituted; Rd is selectedfrom: (a) -Re-Q-(Rf)_(p)(Rg)_(q); or (b) Ar₁-D-Ar₂, wherein  p and q areindependently 0 or 1;  Re is C₁-C₈alkyl or alkylidene and  Re which maybe unsubstituted or substituted;  Q is N, O, S, S(O), or S(O)₂;  Ar₁ andAr₂ are substituted or unsubstituted aryl or het;  Rf and Rg are eachindependently H, —C₁-C₁₀alkyl, C₁-C₁₀alkylaryl, —OH, —O—C₁-C₁₀alkyl,—(CH₂)₀₋₆C₃-C₇cycloalkyl, —O—(CH₂)₀₋₆aryl, phenyl, aryl, phenyl-phenyl,—(CH₂)₁₋₄het, —O—(CH₂)₁₋₆het, —OR₁₁, —C(O)—R₁₁, —C(O)—N(R₁₁)(R₁₂),—N(R₁₁)(R₁₂), —S—R₁₁, —S(O)—R₁₁, —S(O)₂—R₁₁, —S(O)₂—NR₁₁R₁₂,—NR₁₁—S(O)₂—R₁₂, S—C₁-C₁₀alkyl, aryl-C₁-C₄alkyl, het-C₁-C₄-alkyl,wherein alkyl, cycloalkyl, het and aryl are unsubstituted orsubstituted, —SO₂, C₁-C₂alkyl, —SO₂—C₁-C₂alkylphenyl, —O—C₄alkyl, or  Rgand Rf form a ring selected from het or aryl;  D is —CO—,—C(O)—C₁-C₇alkylene or arylene, —CF₂—, —O—, —S(O)_(r), where r is 0-2,1,3-dioaxolane or C₁-C₇alkyl-OH, where alkyl, alkylene or arylene may beunsubstituted or substituted with one or more halogens, OH,—O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃, or  D is —N(Rh), wherein Rh is H,C₁-C₇alkyl (unsubstituted or substituted), aryl, —O(C₁-C₇cycloalkyl)(unsubstituted or substituted), C(O)—C₁-C₁₀alkyl,C(O)—C_(o)-C₁₀alkyl-aryl, C—O—C₁-C₁₀alkyl, C—O—C₁-C₁₀alkyl-aryl orSO₂—C₁-C₁₀-alkyl, SO₂—(C_(o)-C₁₀-alkylaryl); Rc is H, or Rc and Rd maytogether form a cycloalkyl or het, where if Rd and Rc form a cycloalkylor het, R₅ is attached to the formed ring at a C or N atom; R₆, R₇, R₁₆and R₁₇ are each independents H, —C₁-C₁₀alkyl, —C₁-C₁₀alkoxy,aryl-C₁-C₁₀alkoxy, —OH, —O—C₁-C₁₀alkyl, —(CH₂)₀₋₄C₃-C₇cycloalkyl,—O—(CH₂)₀₋₆aryl, phenyl, —(CH₂)₁₋₄het, —O—(CH₂)₁₋₆het, —OR₁₁, —C(O)—R₁₁,—C(O)—N(R₁₁)(R₁₂), —N(R₁₁)(R₁₂), —S—R₁₁, —S(O)—R₁₁, —S(O)₂—R₁₁,—S(O)₂—NR₁₁R₁₂, —NR₁₁—S(O)₂—R₁₂, wherein alkyl, cycloalkyl and aryl areunsubstituted or substituted; and R₆, R₇, R₁₆ and R₁₇ can be united toform a ring system, wherein R₁₁ and R₁₂ are independently H,C₁-C₁₀alkyl, —(CH₂)₀₋₆C₃-C₇cycloalkyl, —(CH₂)₀₋₆(CH)₀₋₁(aryl)₁₋₂,—C(O)—C₁-C₁₀alkyl, —C(O)(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆aryl,—C(O)—(CH₂)₁₋₆O-fluorenyl, —C(O)—NH—(CH₂)₀₋₆aryl, —C(O)—(CH₂)₀₋₆aryl,—C(O)—(CH₂)₁₋₆het, —C(S)—C₁-C₁₀alkyl, —C(S)—(CH₂)₁₋₆C₃-C₇cycloalkyl,—C(S)—O—(CH₂)₀₋₆aryl, —C(S)—(CH₂)₀₋₆O-fluorenyl, —C(S)—NH—(CH₂)₀₋₆aryl,—C(S)—CH₂)₀₋₆aryl, —C(S)(CH₂)₁₋₆het, wherein alkyl, cycloalkyl and arylare unsubstituted or substituted, or R₁₁ and R₁₂ are a substituent thatfacilitates transport of the molecule across a cell membrane, or R₁₁ andR₁₂, together with the nitrogen atom, form het, wherein the alkylsubstituents of R₁₁ and R₁₂ may be unsubstituted or substituted by oneor more substituents selected from C₁-C₁₀alkyl, halogen, OH,—O—C₁-C₆alkyl, —S—C₁-C₆alkyl or —CF₃; substituted cycloalkylsubstituents of R₁₁ and R₁₂ are substituted by one or more substituentsselected from a C₁-C₁₀alkene, C₁-C₆alkyl, halogen, OH, —O—C₁-C₆alkyl,—S—C₁-C₆alkyl or —CF₃; and substituted phenyl or aryl of R₁₁ and R₁₂ aresubstituted by one or more substituents selected from halogen, hydroxy,C₁-C₄alkyl, C₁-C₄alkoxy, nitro, —CN, —O—C(O)—C₁-C₄alkyl and—C(O)—O—C₁-C₄aryl or pharmaceutically acceptable salts thereof or (IV)

wherein R₁ is H; R₂ is H, C₁-C₄alkyl, which is unsubstituted orsubstituted by one or more substituents selected from halogen, —OH, —SH,—OCH₃, —SCH₃, —CN, —SCN and nitro; R₃ is H, —CF₃, —C₂F₅, —CH₂-Z, whereinZ is H, —OH, F, Cl, —CH₃, —CF₃, —CH₂Cl, —CH₂F or —CH₂OH, or R₂ and R₃,together with the nitrogen, form a C₁-C₆heteroaliphatic ring; R₄ isC₁-C₁₆straight-chain alkyl, C₃-C₁₀branched-chain alkyl,—(CH₂)₀₋₆C₃-C₇cycloalkyl, —(CH₂)₁₋₆Z₁, —(CH₂)₀₋₆phenyl and —(CH₂)₀₋₆het,wherein the alkyl, cycloalkyl and phenyl substituents are unsubstitutedor substituted, wherein Z₁ is —N(R₉)—C(O)—C₁-C₁₀alkyl,—N(R₉)—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —N(R₉)—C(O)—(CH₂)₀₋₆phenyl,—N(R₉)—C(O)—(CH₂)₁₋₆het, —C(O)—N(R₁₀)(R₁₁), —C(O)—O—C₁-C₁₀alkyl,—C(O)—O—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆phenyl,—C(O)—O—(CH₂)₁₋₄het, —O—C(O)—C₁-C₁₀alkyl,—O—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —O—C(O)—(CH₂)₀₋₆phenyl,—O—C(O)—(CH₂)₁₋₆het, wherein the alkyl, cycloalkyl and phenylsubstituents are unsubstituted or substituted, wherein R₉ is H, —CH₃,—CF₃, —CH₂OH or CH₂Cl; R₁₀ and R₁₁, are each independently H,C₁-C₄alkyl, C₃-C₇cycloalkyl, —(CH₂)₁₋₆C₃-C₇cycloalkyl, —(CH₂)₀₋₆phenyl,wherein the alkyl, cycloalkyl and phenyl substituents are unsubstitutedor substituted, or R₁₀ and R₁₁, together with the nitrogen, are het; hetis a 5 to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatomsselected from N, O and S, or an 8- to 1,2-membered fused ring systemincluding at least one 5 to 7-membered heterocyclic ring containing 1, 2or 3 heteroatoms selected from N, O and S, which heterocyclic ring orfused ring system is unsubstituted or substituted on a carbon atom byhalogen, hydroxy, C₁-C₄alkyl, C₁-C₄alkoxy, nitro, —O—C(O)—C₁-C₄alkyl or—C(O)—O—C₁-C₄alkyl or on a nitrogen by C₁-C₄alkyl, —O—C(O)—C₁-C₄alkyl or—C(O)—O—C₁-C₄alkyl; X is CH or N; R₅ is H, C₁-C₁₀alkyl, C₃-C₇Cycloalkyl,—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C₁-C₁₀alkylaryl,—(CH₂)₀₋₆C₃-C₇cycloalkyl-(CH₂)₀₋₆phenyl, —(CH₂)₀₋₄CH—((CH₂)₁₋₄phenyl)₂,—(CH₂)₀₋₆CH(phenyl), —C(O)—C₁-C₁₀alkyl, —C(O)—(CH₂)₁₋₄C₃-C₇cycloalkyl,—C(O)—(CH₂)₀₋₆phenyl, —(CH₂)₁₋₄het, —C(O)—(CH₂)₁₋₄het, or R₅ is aresidue of an amino acid, wherein the alkyl, cycloalkyl, phenyl and arylsubstituents are unsubstituted or substituted; R₆ is H, methyl, ethyl,—CF₃, —CH₂OH or —CH₂Cl, or R₅ and R₆, together with the nitrogen, arehet; R₇ and R₈ are cis relative to the acyl substituent at the oneposition of the ring and are each independently H, —C₁-C₁₀alkyl, —OH,—O—C₁-C₁₀alkyl, —(CH₂)₀₋₆C₃-C₇cycloalkyl, —O—(CH₂)₀₋₄aryl, phenyl,—(CH₂)₁₋₆het, —O—(CH₂)₁₋₄het, —N(R₁₂)(R₁₃), —SR₁₂, —S(O)—R₁₂,—S(O)₂—R₁₂, —S(O)₂—NR₁₂R₁₃, wherein the alkyl, cycloalkyl and arylsubstituents are unsubstituted or substituted, wherein R₁₂ and R₁₃ areindependents H, C₁-C₁₀alkyl, —(CH₂)₀₋₆C₃-C₇cycloalkyl,—(CH₂)₀₋₆(CH)₀₋₁(aryl)₁₋₂, —C(O)—C₁-C₁₀alkyl,—C(O)—(CH₂)₁₋₆C₃-C₇cycloalkyl, —C(O)—O—(CH₂)₀₋₆aryl,—C(O)—(CH₂)₀₋₆O-fluorenyl, —C(O)—NH—(CH₂)₀₋₆aryl, —C(O)—(CH₂)₀₋₆aryl,—C(O)—(CH₂)₁₋₄het, wherein the alkyl, cycloalkyl and aryl substituentsare unsubstituted or substituted; or a substituent that facilitatestransport of the molecule across a cell membrane, or R₁₂ and R₁₃,together with the nitrogen, are het and aryl is phenyl or naphthyl whichis unsubstituted or substituted; n is 0, 1 or 2; and (b) at least onetaxane.
 2. A method for treating or preventing a proliferative diseasein a subject in need thereof, comprising co-administration to saidsubject of a therapeutically effective amount of at least one taxane anda compound that inhibit the binding of the Smac protein to IAPs offormula (I) or (IV) according to claim
 1. 3. A pharmaceuticalcombination according to claim 1, for use in a method for treating orpreventing a proliferative disease in a subject in need thereof,comprising co-administration to said subject of a therapeuticallyeffective amount of at least one taxane and a compound that inhibit thebinding of the Smac protein to IAPs of formula (I) or (IV).
 4. Apharmaceutical combination according to claim 1, for use in thepreparation of a medicament for use in a method for treating orpreventing a proliferative disease in a subject in need thereof,comprising co-administration to said subject of a therapeuticallyeffective amount of at least one taxane and a compound that inhibit thebinding of the Smac protein to IAPs of formula (I) or (IV).
 5. Apharmaceutical combination according to claim 1, wherein agent a) isN-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamideof formula (III):


6. A pharmaceutical combination according to claim 1, wherein agent b)is selected from Paclitaxel, docetaxel, vinorelbine and the epothilonesand combinations thereof.
 7. A method for treating a proliferativedisease comprising administering a combination of a taxane and acompound that inhibit the binding of the Smac protein to IAPs of formula(I) or (IV).
 8. A method for treating a proliferative-disease comprisingadministering a combination of a taxane and a compound selected fromN-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3c]pyridin-1-yl-ethyl]-2-methylamino-propionamideof formula (III) and pharmaceutically acceptable salts thereof.
 9. Amethod for treating a proliferative disease comprising administering acombination of a taxane and a compound that inhibit the binding of theSmac protein to IAPs of formula (I) or (IV) wherein the taxane isselected from paclitaxel and docitaxel, and combinations thereof.
 10. Amethod for treating a proliferative disease selected from breast,ovarian and lung tumors comprising administering a combination of ataxane and a compound that inhibit the binding of the Smac protein toInhibitor of Apoptosis Proteins (IAPs) of formula (I) or (IV).
 11. Amethod for treating a proliferative disease selected from breast,ovarian and lung tumors comprising administering a combination of ataxane and a compound selected fromN-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3c]pyridin-1-yl-ethyl]-2-methylamino-propionamideof formula (III) and pharmaceutically acceptable salts thereof.